CD8+ T cells are often essential for immunological tumor rejection but fail to destroy established solid tumors because of a physical or immunological local barrier. The common goal of this project is to understand and overcome the failure of CD8+ T cells to destroy established tumors. In principle, two solid tumor models are being used: (i) spontaneous or chemically induced tumors expressing the directly and/or indirectly presented antigen Ld/SIYRYYGL and (ii) transplanted or primary solid tumors that express the oncogene E6/E7 of HPV. Dr. Schreiber will study - and attempt to counteract - the mechanisms involved in the local physical and/or immunological barrier that may prevent the priming, memory development and attraction of T cells into solid tumors. Dr. Fu will attempt to eliminate the local barrier to priming and attraction of na[unreadable]ve T cells into solid tumors, and he will attempt to improve the entry and proliferation of memory T cells by causing the development of secondary lymphoid structures in solid tumors. He plans to do this by introducing ligands for the lymphotoxin Beta-receptor into the tumor. Dr. Gajewski is devising means and procedures to counter negative regulatory influences on CD8+ T cells occurring in the tumor microenvironment or the circulation by devising T cells that lack negative regulatory receptors or by introducing with a novel adenoviral transduction system anti-apoptotic molecules into T cells that then will be used for adoptive transfer in vivo. Dr. Kast in collaboration with Dr. Nishimura will make normal peripheral T cells tumor-specific by retroviral transduction with T cell receptor genes of HPV E6/E7 specific T cell clones and use these modified T cells to study their efficiency in adoptive transfer on established tumors and lung metastases in mice. Finally, Dr. Meredith (Biochemistry Core) and Dr. Nishimura (Molecular Core) will give advice and guidance on the multiple biochemical and molecular aspects of the program, and provide assays and produce essential reagents, while Dr. Karrison as part of the Statistics Core will give advice in further design and evaluation of the proposed experiments. Thus, the three cores will help the four projects to define conditions and mechanisms by which CD8+ T cell responses can destroy solid established tumors.